Respiratory cycle timing and fast inspiratory discharge rhythms in the adult decerebrate rat

In supracollicular decerebrate paralyzed adult rats, neural respiration was monitored by bilateral phrenic recordings. In the study of respiratory cycle timing, the effects of vagal afferent input (lung inflation) on respiratory phase durations resembled those seen in decerebrate cats. 1) Withholding lung inflation during neural inspiration (I) produced lengthening of I phase duration by 46% (mean, n = 11). 2) Maintaining lung inflation during neural expiration (E) produced lengthening of E phase duration by 112% (mean, n = 4). In the study of fast rhythms in inspiratory discharges, phrenic nerve autospectra and bilateral (left-right) phrenic coherences in 16 rats revealed two types of fast rhythm: 1) high-frequency oscillation (HFO), which had significant coherence peaks (n = 9, range 106-160 Hz, mean 132 Hz); and 2) medium-frequency oscillation (MFO), which had autospectral peaks but no distinct coherence peaks (n = 11, range 46-96 Hz, mean 66 Hz). These rhythms resembled MFOs and HFOs in the decerebrate cat, but the modal frequency range was about twice as large. In addition, these frequency values differed markedly from the 20-40 Hz of the rhythms found in earlier studies in neonatal in vitro preparations; the difference may be due to developmental immaturity.     

Defects in mitochondrial respiratory complexes III and IV,and human pathologies

Here, relationships between alterations in tissue-specific content, protein structure, activity, and/or assembly of respiratory complexes III and IV induced by mutations in corresponding genes and various human pathologies are reviewed. Cytochrome bc(1) complex and cytochrome c oxidase (COX) deficiencies have been detected in a heterogeneous group of neuromuscular and non-neuromuscular diseases in childhood and adulthood, presenting a number of clinical phenotypes of variable severity. Such disorders can be caused by mutations located either in mitochondrial genes or in nuclear genes encoding structural subunits of the complexes or corresponding assembly factors/chaperones. Of the defects in mitochondrial DNA genes, mutations in cytochrome b subunit of complex III, and in structural subunits I-III of COX have been described to date. As to defects in nuclear DNA genes, mutations in genes encoding the complexes assembly factors such as the BCS1L protein for complex III; and SURF-1, SCO1, SCO2, and COX10 for complex IV have been identified so far.     

A two-scale approach for CFD modeling of endovascular Chemofilter device

Two-scale CFD modeling is used to design and optimize a novel endovascular filtration device for removing toxins from flowing blood. The Chemofilter is temporarily deployed in the venous side of a tumor during the intra-arterial chemotherapy in order to filter excessive chemotherapy drugs such as Doxorubicin from the blood stream. The device chemically binds selective drugs to its surface thus filtering them from blood, after they have had the effect on the tumor and before they reach the heart and other organs. The Chemofilter consists of a porous membrane made of microscale architected materials and is installed on a structure similar to an embolic protection device. Simulations resolving the microscale structure of the device were carried out to determine the permeability of the microcell membrane. The resulting permeability coefficients were then used for macroscale simulations of the flow through the device modeled as a porous material. The microscale simulations indicate that greater number of microcell layers and smaller microcell size result in increased pressure drop across the membrane, while providing larger surface area for drug binding. In the macroscale simulations, the study of idealized prototypes show that the pressure drop can be reduced by increasing the membrane’s tip angle and by decreasing the number of membrane’s sectors. Such design, however, can conversely affect the overall drug binding. By decreasing the concentration of toxins in the cardiovascular system, the drug dosage can be increased while side effects are reduced, thus improving the effectiveness of treatment.     

Sensitivity of IgG-ELISA for Detecting Airborne Pollen Antigens of Betulaceae

Pollen sculpture elements of four Rhododendron species from 49 populations were studied using scanning electron microscopy. The sculpture in the polar areas of the studied taxa pollen differed in type, shape, size, and distribution of individual elements. There were five sculpture types identified. The pollen of Rhododendron ledebourii from various populations in Altai revealed sculpture elements characteristic of R. dauricum, R. mucronulatum, and R. sichotense, questioning the taxonomic position of the former species. Analysis of the geographical distribution of sculpture types clarified species boundaries and zones of sympatric distribution. The northern boundary of R. mucronulatum was expanded and new populations of R. sichotense were revealed. In the sympatric zones of R. mucronulatum and R. sichotense, there were intermediate populations showing pollen sculptures typical of R. dauricum, R. mucronulatum, and R. sichotense. The sculpture diversity observed in the pollen of R. dauricum, together with its presence in sympatric zones, suggests that it is probably a hybrid of R. sichotense and R. mucronulatum or a subspecies of R. sichotense.     

The low-resolution structure of nHDL reconstituted with DMPC with and without cholesterol reveals a mechanism for particle expansion

Small-angle neutron scattering (SANS) with contrast variation was used to obtain the low-resolution structure of nascent HDL (nHDL) reconstituted with dimyristoyl phosphatidylcholine (DMPC) in the absence and presence of cholesterol, [apoA1:DMPC (1:80, mol:mol) and apoA1:DMPC:cholesterol (1:86:9, mol:mol:mol)]. The overall shape of both particles is discoidal with the low-resolution structure of apoA1 visualized as an open, contorted, and out of plane conformation with three arms in nascent HDL/dimyristoyl phosphatidylcholine without cholesterol (nHDL_DMPC) and two arms in nascent HDL/dimyristoyl phosphatidylcholine with cholesterol (nHDL_DMPC+Chol). The low-resolution shape of the lipid phase in both nHDL_DMPC and nHDL_DMPC+Chol were oblate ellipsoids, and fit well within their respective protein shapes. Modeling studies indicate that apoA1 is folded onto itself in nHDL_DMPC, making a large hairpin, which was also confirmed independently by both cross-linking mass spectrometry and hydrogen-deuterium exchange (HDX) mass spectrometry analyses. In nHDL_DMPC+Chol, the lipid was expanded and no hairpin was visible. Importantly, despite the overall discoidal shape of the whole particle in both nHDL_DMPC and nHDL_DMPC+Chol, an open conformation (i.e., not a closed belt) of apoA1 is observed. Collectively, these data show that full length apoA1 retains an open architecture that is dictated by its lipid cargo. The lipid is likely predominantly organized as a bilayer with a micelle domain between the open apoA1 arms. The apoA1 configuration observed suggests a mechanism for accommodating changing lipid cargo by quantized expansion of hairpin structures.     

Computational modeling of drug transport and mixing in the chemofilter device: enhancing the removal of chemotherapeutics from circulation

Biomechanics and Modeling in Mechanobiology - Intra-arterial chemotherapy (IAC) is the preferred treatment for non-resectable hepatocellular carcinoma. A large fraction of IAC drugs, e.g.,...     

Estimation of human circadian phase via a multi-channel ambulatory monitoring system and a multiple regression model

Reliable detection of circadian phase in humans using noninvasive ambulatory measurements in real-life conditions is challenging and still an unsolved problem. The masking effects of everyday behavior and environmental input such as physical activity and light on the measured variables need to be considered critically. Here, we aimed at developing techniques for estimating circadian phase with the lowest subject burden possible, that is, without the need of constant routine (CR) laboratory conditions or without measuring the standard circadian markers, (rectal) core body temperature (CBT), and melatonin levels. In this validation study, subjects (N = 16) wore multi-channel ambulatory monitoring devices and went about their daily routine for 1 week. The devices measured a large number of physiological, behavioral, and environmental variables, including CBT, skin temperatures, cardiovascular and respiratory function, movement/posture, ambient temperature, and the spectral composition and intensity of light received at eye level. Sleep diaries were logged electronically. After the ambulatory phase, subjects underwent a 32-h CR procedure in the laboratory for measuring unmasked circadian phase based on the "midpoint" of the salivary melatonin profile. To overcome the complex masking effects of confounding variables during ambulatory measurements, multiple regression techniques were applied in combination with the cross-validation approach to subject-independent prediction of circadian phase. The most accurate estimate of circadian phase was achieved using skin temperatures, irradiance for ambient light in the blue spectral band, and motion acceleration as predictors with lags of up to 24 h. Multiple regression showed statistically significant improvement of variance of prediction error over the traditional approaches to determining circadian phase based on single predictors (motion acceleration or sleep log), although CBT was intentionally not included as the predictor. Compared to CBT alone, our method resulted in a 40% smaller range of prediction errors and a nonsignificant reduction of error variance. The proposed noninvasive measurement method could find applications in sleep medicine or in other domains where knowing the exact endogenous circadian phase is important (e.g., for the timing of light therapy).     

The low resolution structure of ApoA1 in spherical high density lipoprotein revealed by small angle neutron scattering

Spherical high density lipoprotein (sHDL), a key player in reverse cholesterol transport and the most abundant form of HDL, is associated with cardiovascular diseases. Small angle neutron scattering with contrast variation was used to determine the solution structure of protein and lipid components of reconstituted sHDL. Apolipoprotein A1, the major protein of sHDL, forms a hollow structure that cradles a central compact lipid core. Three apoA1 chains are arranged within the low resolution structure of the protein component as one of three possible global architectures: (i) a helical dimer with a hairpin (HdHp), (ii) three hairpins (3Hp), or (iii) an integrated trimer (iT) in which the three apoA1 monomers mutually associate over a portion of the sHDL surface. Cross-linking and mass spectrometry analyses help to discriminate among the three molecular models and are most consistent with the HdHp overall architecture of apoA1 within sHDL.     

Temperature and state dependence of dynamic phrenic oscillations in the decerebrate juvenile rat

The aim of the present study was to determine characteristics of fast oscillations in the juvenile rat phrenic nerve (Ph) and to establish their temperature and state dependence. Two different age-matched decerebrate, baro- and chemodenervated rat preparations, in vivo and in situ arterially perfused models, were used to examine three systemic properties: 1) generation and dynamics of fast oscillations in Ph activity (both preparations), 2) responses to anoxia (both preparations), and 3) the effects of temperature on fast oscillations (in situ only). Both juvenile preparations generated power and coherence in two major bands analogous to adult medium- and high-frequency oscillations (HFO) at frequencies that increased with temperature but were lower than in adults. At < 28 degrees C, however, Ph oscillations were confined primarily to one low-frequency band (20-45 Hz). During sustained anoxia, both preparations produced stereotypical state changes from eupnea to hyperpnea to transition bursting (a behavior present only in vivo during incomplete ischemia) to gasping. Thus the juvenile rat produces a sequential pattern of responses to anoxia that are intermediate forms between those produced by neonates and those produced by adults. Time-frequency analysis determined that fast oscillations demonstrated dynamics over the course of the inspiratory burst and a state dependence similar to that of adults in vivo in which hyperpnea (and transition) bursts are associated with increases in HFO, while gasping contains no HFO. Our results confirm that both the fast oscillations in Ph activity and the coherence between Ph pairs produced by the juvenile rat are profoundly state- and temperature-dependent.